2013年7月20日 讯 /生物谷BIOON/ --近日,来自悉尼Garvan医学研究所的研究人员通过研究表示,对单一基因突变的免疫缺陷患者进行研究或许可以获取更多关于免疫系统研究的信息,尤其是当患者实际的针状和临床预期不太一样的时候,就更要去深入研究其中的机制,相关研究刊登于国际杂志Journal of Allergy and Clinical Immunology上。
文章中,研究者对常染色体显性高IgE综合征进行了研究,该疾病是基因STAT3发生突变导致的,这使得患者更易发生淋巴瘤,实验室和动物模型研究预测这种疾病的患者对病毒和癌症会更加易感,而实际情况并不是这样。
研究人员Megan Ives及其同事研究发现,常染色体显性高IgE综合征个体相比预期来说,其免疫系统具有更强的代偿能力,研究者预测患者机体中会较少产生具有功能的杀伤性T细胞,杀伤性T细胞是一种可以杀灭入侵微生物和癌症细胞的机体免疫细胞。
研究者Elissa Deenick说道,在正常情况下STAT3分子可以在T细胞中传输生化信号,这种信号可以指导STAT3分子开启其杀灭功能,但是在高IgE病人中,其由于缺少STAT3基因,这种信号大部分时间采用“声东击西的策略”,看似工作实际上并无功能。杀伤性T细胞需要特定的分子来变得更为有效,尤其是对付病毒和淋巴瘤;而高IgE患者就不能产生必备的信号来产生这些效应分子。
研究者认为这项研究非常重要,因为其揭示了通过小鼠模型获得的结果和人类真正感染后的结果二者之间的差异;研究者的研究工作可以帮助我们理解为何高IgE病人的情况并不是不好,不好的情况只是研究者对其病情的预测而已;研究结果对于临床研究非常重要,因为其为我们提供了病人实际的情况,方便医生们根据实际病情进行治疗。(生物谷Bioon.com)
doi:10.1016/j.jaci.2013.05.029
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PMID:
Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8+ T-cell memory formation and function
Megan L. Ives, BAdvSc , Cindy S. Ma, PhD , Umaimainthan Palendira, PhD , Anna Chan, MSc , Jacinta Bustamante, MD, PhD , Stephanie Boisson-Dupuis, PhD , Dan Engelhard, MD , Diana Averbuch, MD , Klaus Magdorf, MD , Joachim Roesler, MD, PhD , Jane Peake, MBBS , Melanie Wong, MBBS, PhD, FRCPA , Sharon Choo, MBBS, FRACP, FRCPA , Matthew C. Cook, MBBS, PhD, FRACP, FRCPA , Capucine Picard, MD, PhD , Anne Durandy, MD, PhD , Miyuki Tsumura, MSc , Masao Kobayashi, MD, PhD , Gulbu Uzel, MD , Jean-Laurent Casanova, MD, PhD , Stuart G. Tangye, PhD , Elissa K. Deenick, PhD
Background The capacity of CD8+ T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8+ T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8+ T-cell immunity in human subjects is unknown. Objective We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8+ T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. Methods Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8+ T-cell differentiation in vivo and in vitro. Results Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8+ T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21–stimulated naive CD8+ T cells. However, this defect was overcome by T-cell receptor engagement. Conclusion The IL-21R/STAT3 pathway is required for many aspects of human CD8+ T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R–deficient subjects.